The present invention relates to novel carboxylic acid derivatives, their preparation and use.
Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. xe2x80x9cEndothelinxe2x80x9d or xe2x80x9cETxe2x80x9d hereinafter refers to one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on vessel tone. It is known that this vasoconstriction is caused by binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
Elevated or abnormal release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which may result in disorders. As reported in the literature, endothelin is involved in a number of disorders. These include: hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud""s syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, athersclerosis and asthma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 328, 1732 (1993), Nephron 66, 373 (1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995); Cancer Research 56, 663 (1996)).
At least two endothelin receptor subtypes, ETA and ETB receptors, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, substances which inhibit the binding of endothelin to the two receptors ought to antagonize the physiological effects of endothelin and therefore represent valuable drugs.
Mixed ETA/ETB receptor antagonists have been described in DE Patent Application 19636046.3. The spacer Q (see formula II) is important for these compounds, corresponds in length to a C2-C4-alkyl chain and has the function of producing a defined distance between R6 and W in compounds of the formula II. 
Furthermore, in the patent application WO 97/38980, the following compounds of the formula VII are described as endothelin receptor antagonists: 
An advantage of these compounds is -said to be the low plasma binding.
We have now found, surprisingly, that the receptor affinity and selectivity can be influenced using the spacer Q=R6CR7R8 (see formula I), as a function of R6=amide. Thus, either ETA-selective, ETB-selective or else mixed receptor antagonists [sic] can be prepared.
The antagonists referred to here as ETA (ETB)-specific antagonists are those whose affinity for the ETA (ETB) receptor is at least ten times higher than their affinity for the ETB (ETA) receptor. Preferred compounds are those whose difference in affinity for the two receptors is at least twenty.
Mixed endothelin receptor antagonists are those compounds which bind with approximately the same affinity to the ETA and ETB receptors. Approximately the same affinity for receptors exists when the ratio of the affinities is greater than 0.05 (preferably 0.1) and less than 20 (preferably 10).
It is an object of the present invention to identify compounds which belong to one of the three selectivity groups.
We have found that this object is achieved by carboxylic acid derivatives of the formula I 
[lacuna] R1 is tetrazole [sic] or a group 
where R has the following meaning:
a) a radical OR9 where R9 is:
hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerated organic ammonium ion such as tertiary C1-C4-alkylammonium or the ammonium ion;
C3-C8-cycloalkyl, C1-C8-alkyl, CH2-phenyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
a C3-C6-alkenylxe2x80x94or a C3-C6-alkynyl group, it being possible for these groups in turn to carry one to five halogen atoms;
R9 can also be a phenyl radical which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
b) a 5-membered heteroaromatic system which is linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one or two halogen atoms, or one or two C1-C4-alkyl or one or two C1-C4-alkoxy groups.
c) a group 
xe2x80x83where k can assume the values 0, 1 and 2, p can assume the values 1, 2, 3 and 4, and R10 is
C1-C4-alkyl, C3-C8-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or phenyl, which can be substituted by one or more, e.g. one to three, of the following radicals:
halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2.
d) a radical 
xe2x80x83where R11 is:
C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, it being possible for these radicals to carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical as specified under c);
phenyl, which can be substituted by one to three of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 
The other substituents have the following meanings:
R2 hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio, or CR2 is linked to CR10 as indicated under Z to give a 5- or 6-membered ring.
X nitrogen or methine.
Y nitrogen or methine.
Z nitrogen or CR12, where R12 is hydrogen, halogen or C1-C4-alkyl, or CR12 forms together with CR2 or CR3 a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C1-C4-alkyl groups and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, xe2x80x94NH or N(C1-C4-alkyl).
At least one of the ring members X, Y or Z is nitrogen.
R3 hydrogen, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, C1-C4-alkylthio, or CR3 is linked to CR12 as indicated under Z to give a 5- or 6-membered ring.
R4 and R5 (which can be identical or different):
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenoxy, carboxyl, C1-C4-haloalkoxy, C1-C4-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or phenyl which can be substituted one or more times, e.g. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio; or
phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene, or ethenylene group, an oxygen or sulfur atom or an SO2, NH or N-alkyl group;
C3-C8-cycloalkyl.
R6 a group 
R13 and R14 (which can be identical or different):
hydrogen, with the proviso that R13 and R14 must not simultaneously be hydrogen,
C1-C8-alkyl, C3-C8-alkenyl or C3-C8-alkynyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, amino, carboxamide [sic], cyano, C1-C4-alkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C3-C8-alkylcarbonylalkyl, C3-C8-cycloalkyl, 1-indanyl, 2-indanyl, 1-tetrahydronaphthyl, 2-tetrahydronaphthyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, phenoxy or phenyl, it being possible for said aryl radicals in turn to be substituted one or more times, e.g. one to three times, by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, or C1-C4-alkylthio;
C3-C8-cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkoxy;
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, carboxamide [sic], mercapto, carboxyl, cyano, hydroxyl, amino, R15, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C1-C4-haloalkyl, C3-C6-alkynyloxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene [sic], dioxoethylene [sic] or phenyl, which can be substituted onr or more times, e.g. one to three times, by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
or R13 and R14 together form a C3-C7-alkylene chain which is closed to a ring and which can be substituted one or more times by C1-C4-alkyl, C1-C4-alkylthio, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, and in which one alkylene [sic] group can be replaced by oxygen, sulfur, nitrogen or N(C1-C4-alkyl), such as xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, xe2x80x94(CH2)7xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Sxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94NHxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)2xe2x80x94;
or R13 and R14 together form a C3-C7-alkylene chain or C4-C7-alkenylene chain, which is closed to a ring and each of which can be substituted one to three times by C1-C4-alkyl and to each of which is fused a phenyl ring which can be substituted one or more times by halogen, C1-C4-alkyl, C1-C4-alkylthio, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, hydroxyl, carboxyl, amino, carboxamide [sic].
R7 and R8 (which can be identical or different):
hydrogen, C1-C4-alkyl.
R15 C1-C4-alkyl, C1-C4-alkylthio, C1-C4-alkoxy, each of which carry one of the following radicals: hydroxyl, carboxyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, carboxamide [sic] or CON(C1-C4-alkyl)2.
R18 hydrogen;
C1-C8-alkyl, C3-C8-alkenyl or C3-C8-alkynyl, where each of these radicals can be substituted one or more times by: halogen, carboxyl, cyano, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C3-C8-cycloalkyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, phenoxy or phenyl, where the abovementioned aryl radicals for their part can be substituted one or more times, for example one to three times by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, or C1-C4-alkylthio;
C3-C8-cycloalkyl, where each of these radicals can be substituted one or more times by: halogen, C1-C4-alkyl;
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, R15, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
R19 C1-C8-alkylcarbonyl, C2-C8-alkenylcarbonyl or C2-C8-alkynylcarbonyl, where each of these radicals can be substituted one or more times by: halogen, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, C3-C8-cycloalkyl, phenoxy or phenyl, where the abovementioned aryl radicals for their part can be substituted one or more times, for example one to three times by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, or C1-C4-alkylthio;
benzyloxycarbonyl, C3-C8-cycloalkylcarbonyl, where each of these radicals can be substituted one or more times by: halogen, C1-C4-alkyl;
phenylcarbonyl or naphthylcarbonyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, R15, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C1-C4-haloalkyl, C3-C6-alkynyloxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted one or more times, for example one to three times by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
C1-C8-alkylsulfonyl, C3-C8-alkenylsulfonyl or C3-C8-alkynylsulfonyl, where each of these radicals can be substituted one or more times by: halogen, C1-C4-alkoxy, phenyl, where the abovementioned aryl radical for its part can be substituted one or more times, for example one to three times by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, or C1-C4-alkylthio;
C3-C8-cycloalkylsulfonyl;
phenylsulfonyl or naphthylsulfonyl, each of which can be substituted by one or more of the following radicals: halogen, cyano, hydroxyl, amino, R15, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C1-C4-haloalkyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, C1-C4-haloalkoxy, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted one or more times, for example one to three times by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio.
R20 hydrogen;
C1-C4-alkyl, where each of these radicals can be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, amino, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, C3-C8-cycloalkyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, indolyl, phenoxy or phenyl, where the abovementioned aryl radicals for their part can be substituted one or more times, for example one to three times by halogen, hydroxyl, mercapto, carboxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2 or C1-C4-alkylthio.
R21 hydrogen, C1-C4-alkyl.
W sulfur or oxygen.
In these cases and hereinafter, the following definitions apply:
An alkali metal is, for example, lithium, sodium, potassium;
An alkaline earth metal is, for example, calcium, magnesium, barium;
C3-C8-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
C1-C4-haloalkyl can be linear or branched such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;
C1-C4-haloalkoxy can be linear or branched such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;
C1-C4-alkyl can be linear or branched such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;
C2-C4-alkenyl can be linear or branched such as ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl;
C2-C4-alkynyl can be linear or branched such as ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
C1-C4-alkoxy can be linear or branched such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;
C3-C6-alkenyloxy can be linear or branched such as allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;
C3-C6-alkynyloxy can be linear or branched such as 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;
C1-C4-alkylthio can be linear or branched such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;
C1-C4-alkylcarbonyl can be linear or branched such as acetyl, ethylcarbonyl or 2-propylcarbonyl, 1-propylcarbonyl, 1-butylcarbonyl;
C1-C4-alkoxycarbonyl can be linear or branched such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;
C3-C8-alkylcarbonylalkyl can be linear or branched such as 2-oxo-1-propyl, 3-oxo-1-butyl or 3-oxo-2-butyl
C1-c8-alkyl can be linear or branched such as C1-C4-alkyl, pentyl, hexyl, heptyl or octyl;
C1-C8-alkylcarbonyl can be linear or branched such as C1-C4-alkylcarbonyl, 1-pentylcarbonyl, 1-hexylcarbonyl, 1-heptylcarbonyl or 1-octylcarbonyl;
C2-C8-alkenylcarbonyl can be linear or branched such as ethenylcarbonyl, 1-propen-3-ylcarbonyl, 1-propen-2-ylcarbonyl, 1-propen-1-ylcarbonyl, 2-methyl-1-propenylcarbonyl, 1-buten-1-ylcarbonyl, 1-penten-1-ylcarbonyl, 1-octen-1-ylcarbonyl;
C2-C8-alkynylcarbonyl can be linear or branched such as ethynylcarbonyl, 1-propyn-3-ylcarbonyl, 1-propyn-1-ylcarbonyl, 1-butyn-1-ylcarbonyl, 1-pentyn-1-ylcarbonyl, 1-octyn-1-ylcarbonyl;
C3-C8-cycloalkylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 4-methylcyclohex-1-ylcarbonyl, cycloheptylcarbonyl or cyclooctylcarbonyl;
C1-C4-alkylsulfonyl can be linear or branched such as methylsulfonyl, ethylsulfonyl or 2-propylsulfonyl, 1-propylsulfonyl, 2-methyl-1-propylsulfonyl, 1-butylsulfonyl;
C1-C8-alkylsulfonyl can be linear or branched such as C1-C4-alkylsulfonyl, 1-pentylsulfonyl, 1-hexylsulfonyl, 1-heptylsulfonyl or 1-octylsulfonyl;
C3-C8-alkenylsulfonyl can be linear or branched such as 1-propen-3-ylsulfonyl, 1-propen-2-ylsulfonyl, 1-propen-1-ylsulfonyl, 2-methyl-1-propen-1-ylsulfonyl, 1-buten-1-ylsulfonyl, 1-penten-1-ylsulfonyl, 1-octen-1-ylsulfonyl;
C3-C8-alkynylsulfonyl can be linear or branched such as 1-propyn-3-ylsulfonyl, 1-propyn-1-ylsulfonyl, 1-butyn-1-ylsulfonyl, 1-pentyn-1-ylsulfonyl, 1-octyn-1-ylsulfonyl;
C3-C8-cycloalkylsulfonyl is, for example, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, 4-methylcyclohex-1-ylsulfonyl, cycloheptylsulfonyl or cyclooctylsulfonyl;
halogen is, for example, fluorine, chlorine, bromine, iodine.
The invention further relates to those compounds from which the compounds of the formula I can be liberated (called prodrugs).
Preferred prodrugs are those for which the liberation takes place under conditions like those prevailing in certain compartments of the body, e.g. in the stomach, intestine, bloodstream, liver.
The compounds I and the intermediates for preparing them, such as III, IV and V, may have one or more asymmetrically substituted carbon atoms. Compounds of this type can exist as pure enantiomers or pure diastereomers or as mixture thereof. The use of an enantiomerically pure compound as active ingredient is preferred.
The invention further relates to the use of the abovementioned carboxylic acid derivatives for producing drugs, in particular for producing inhibitors for ETA and ETB receptors. The compounds according to the invention are suitable as selective and as mixed antagonists as have been defined at the outset.
Compound of the formula V where W is sulfur or oxygen can be prepared as described in WO 96/11914. 
Compounds of the formula V can be obtained in enantiomerically pure form by starting from enantiomerically pure compounds of the formula III and reacting them with compounds of the formula IV as described in WO 96/11914.
It is additionally possible to obtain enantiomeric compounds of the formula V by subjecting racemic or diastereomeric compounds of the formula V to a conventional racemate resolution using suitable enantiomerically pure bases. Examples of suitable bases of this type are 4-chlorophenylethylamine and the bases mentioned in WO 96/11914.
It is moreover possible to obtain enantiomerically pure compounds of the formula V by acid-catalyzed transetherification as described in DE 19636046.3.
The preparation of compounds of the formula III has been described in WO 96/11914, whereas compounds of the formula IVa (R6=amide) or IVb (R6=sulfonamide/amide) either are known or can be synthesized by generally known methods, such as: 
The compounds according to the invention in which the substituents have the meanings stated under formula I can be prepared, for example, by reacting the carboxylic acid derivatives of the formula V in which the substituents have the stated meanings with compounds of the formula VI. 
In formula VI, R16 is halogen or R17xe2x80x94SO2xe2x80x94, where R17 can be C1-C4-alkyl, C1-C4-haloalkyl or phenyl. In addition, at least one of the ring members X or Y or Z is nitrogen. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, ie. a base which deprotonates the intermediate V, at a temperature in the range from room temperature to the boiling point of the solvent.
Compounds of type I with R1=COOH can be obtained directly in this way if the intermediate V where R1 is COOH is deprotonated with two equivalents of a suitable base and reacted with compounds of the formula V. This reaction also takes place in an inert solvent and at a temperature in the range from room temperature to the boiling point of the solvent. Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers, such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones, for example dimethyl sulfoxide and sulfolane.
Compounds of the formula VI are known, some of them can be bought or they can be prepared in a generally known manner.
It is possible to use as base an alkali metal or alkaline earth metal hydride such as sodium hydride potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide.
Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie. compounds of the formula I where R1 is COOH, and first converting them in a conventional way into an activated form such as an acid halide, an anhydride or imidazolide, and then reacting the latter with an appropriate hydroxyl compound HOR9. This reaction can be carried out in conventional solvents and often requires addition of a base, in which case those mentioned above are suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as a carbodiimide.
It is additionally possible to prepare compounds of the formula I also by starting from salts of the corresponding carboxylic acids, ie. from compounds of the formula I where R1 is a group COOM where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula Rxe2x80x94A, where A is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or unsubstituted or halogen-, alkyl- or haloalkyl-substituted aryl- or alkylsulfonyl such as toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of the formula Rxe2x80x94A having a reactive substituent A are known or can easily be obtained with general expert knowledge. This reaction can be carried out in conventional solvents and is advantageously undertaken with addition of a base, in which case those mentioned above are suitable.
It is necessary in some cases for preparing the compounds I according to the invention to use generally known protective group techniques. If, for example, R13 is 4-hydroxyphenyl, the hydroxyl group can be initially protected as benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.
Compounds of he formula I where R1 is tetrazole [sic] can be prpared as described in WO 96/11914.
With a view to the biological effect, preferred carboxylic acid derivatives of the formula I, both as pure enantiomers and pure diastereomers and as mixture thereof, are those where the substituents have the following meanings:
R2 hydrogen, hydroxyl, halogen, N(C1-C4-alkyl)2, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-hydroxyalkyl, or CR2 is linked to CR12 as indicated under Z to give a 5- or 6-membered ring;
X nitrogen or methine;
Y nitrogen or methine;
Z nitrogen or CR12, where R12 is hydrogen, fluorine or C1-C4-alkyl, or CR12 forms together with CR2 or CR3 a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two methyl groups and in each of which a methylene group can be replaced by oxygen or sulfur, such as xe2x80x94CH2-CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2-CH2-CH2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2Oxe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90C(CH3)xe2x80x94Oxe2x80x94, xe2x80x94C(CH3)xe2x95x90C(CH3)xe2x80x94Oxe2x80x94, or xe2x80x94C(CH3)xe2x95x90C(CH3)xe2x80x94S;
At least one of the ring members X, Y or Z is nitrogen.
R3 hydrogen, hydroxyl, halogen, N(C1-C4-alkyl)2, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-haloalkoxy, or CR3 is linked to CR10 as indicated under Z to give a 5- or 6-membered ring;
R4 and R5 (which may be identical or different):
phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, cyano, hydroxyl, mercapto, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2 or phenyl which may be substituted one or more times, e.g. one to three times, by halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio; or
phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2xe2x80x94, NHxe2x80x94 or N-alkyl group
C3-C8-cycloalkyl;
R6 a group 
xe2x80x83where the molecular weight of the groups R13 and R14 taken together must be at least 60.
R13 and R14 (which may be identical or different):
hydrogen, C1-C8-alkyl, C3-C8-alkenyl or C3-C8-alkynyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C3-C8-cycloalkyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, phenoxy or phenyl, it being possible for said aryl radicals in turn to be substituted once to three tiems by halogen, hydroxyl, carboxyl, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, N(C1-C4-alkyl)2, or C1-C4-alkylthio;
C3-C8-cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, cyano, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkoxy;
phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, carboxyl, hydroxyl, amino, R15, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxy, phenoxy, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted once to three times by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
or R13 and R14 together form a C3-C7-alkylene chain which is closed to a ring and which may be substituted one or more times by C1-C4-alkyl, C1-C4-haloalkyl, and in which one alkylene [sic] group can be replaced by oxygen or sulfur, such as xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, xe2x80x94(CH2)7xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Sxe2x80x94(CH2)2xe2x80x94;
or R13 and R14 together form a C3-C7-alkylene chain or C4-C7-alkenylene chain which is closed to a ring and to which a phenyl ring is fused, such as 7-azabicyclo[4.2.0]octa-1,3,5-triene, 2,3-dihydroindole, indole, 1,3-dihydroisoindole, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, it being possible for the phenyl ring in each case to be substituted once to three times by halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, hydroxyl, carboxyl.
The molecular weight of the groups R13 and R14 taken together must be at least 46.
R7 and R8 (which may be identical or different):
hydrogen, C1-C4-alkyl.
R15 C1-C4-alkyl, C1-C4-alkoxy, each of which may carry one of the following radicals: hydroxyl, carboxyl, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, carboxamide [sic] or CON(C1-C4-alkyl)2.
R18 hydrogen;
C1-C4-alkyl, C3-C4-alkenyl or C3-C4-alkynyl, where each of these radicals can be substituted one or more times by: halogen, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkoxy, C3-C8-cycloalkyl, phenoxy or phenyl, where the abovementioned aryl radicals for their part can be substituted one or more times, for example one to three times by halogen, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-alkylthio;
C3-C8-cycloalkyl, where each of these radicals can be substituted one or more times by: C1-C4-alkyl;
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, hydroxyl, R15, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, C1-C4-alkylthio, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted one or more times, for example one to three times by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy;
R19 C1-C4-alkylcarbonyl, C2-C4-alkenylcarbonyl or C2-C4-alkynylcarbonyl, where each of these radicals can be substituted one or more times by: halogen, C1-C4-alkoxy, C3-C8-cycloalkyl, phenoxy or phenyl, where the abovementioned aryl radicals for their part can be substituted one or more times, for example one to three times by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-alkylthio;
C3-C8-cycloalkylcarbonyl, where each of these radicals can be substituted one or more times by: C1-C4-alkyl;
phenylcarbonyl or naphthylcarbonyl, each of which can be substituted by one or more of the following radicals: halogen, cyano, hydroxyl, R15, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, phenoxy, C1-C4-alkylthio, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted one or more times, for example one to three times by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or C1-C4-alkylthio;
C1-C4-alkylsulfonyl, where each of these radicals can be substituted one or more times by: halogen, C1-C4-alkoxy, phenyl, where the abovementioned aryl radical for its part can be substituted one to three times by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-alkylthio;
C3-C8-cycloalkylsulfonyl; phenylsulfonyl or naphthylsulfonyl, each of which can be substituted by one or more of the following radicals: halogen, cyano, R15, C1-C4-alkyl, C1-C4-alkoxy, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted one to three times by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-alkylthio;
R20 hydrogen;
C1-C4-alkyl, where each of these radicals can be monosubstituted by: hydroxyl, mercapto, carboxyl, amino, C3-C8-cycloalkyl, indolyl, phenoxy or phenyl, where the abovementioned aryl radicals for their part can be substituted one to three times by halogen, hydroxyl, mercapto, carboxyl, C1-C4-alkyl, C1-C4-alkoxy, amino or C1-C4-alkylthio.
R21 hydrogen, C1-C4-alkyl.
W sulfur or oxygen;
Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those where the substituents have the following meanings:
R2 trifluoromethyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, hydroxymethyl, or CR2 is linked to CR12 as indicated under Z to give a 5- or 6-membered ring;
X nitrogen or methine;
Y nitrogen or methine;
Z nitrogen or CR12 where R12 are [sic] hydrogen, fluorine or C1-C4-alkyl, or CR12 forms together with CR2 or CR3 einen 5- or 6-membered alkylene or alkenylene ring which may be substituted by one or two methyl groups, and in each of which one methylene group can be replaced by oxygen or sulfur, such as xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94, xe2x80x94C(CH3)xe2x95x90C(CH3)xe2x80x94Oxe2x80x94;
at least one of the ring members X, Y or Z is nitrogen;
R3 trifluoromethyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, hydroxymethyl, or CR3 is linked to CR12 as indicated under Z to give a 5- or 6-membered ring;
R4 and R5 (which may be identical or different):
phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, phenoxy or phenyl, which may be substituted once to three times by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-haloalkoxy; or
phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2xe2x80x94, NHxe2x80x94 or N-alkyl group
C5-C7-cycloalkyl;
R6 a group 
xe2x80x83where the molar weight of the groups R13 and R14 taken together must be at least 60.
R13 and R14 (which may be identical or different):
hydrogen, C1-C5-alkyl, C3-C5-alkenyl or C3-C5-alkynyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, carboxyl, amino, C1-C4-alkoxy, C1-C4-haloalkoxy, C5-C6-cycloalkyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, phenoxy or phenyl, it being possible for said aryl radicals in turn to be substituted one to three times by halogen, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, N(C1-C4-alkyl)2;
C3-C8-cycloalkyl, it being possible for each of these radicals to be substituted one or more times by: halogen, carboxyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkoxy;
phenyl which can be substituted one to three times by: halogen, carboxyl, hydroxyl, amino, R15, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxy, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted once to three times by halogen, C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkylthio;
or R13 and R14 together form a C3-C7-alkylene chain which is closed to a ring and which may be substituted one or more times by C1-C4-alkyl and in which one alkylene [sic] group can is be replaced by oxygen or sulfur, such as xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, xe2x80x94(CH2)7xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Sxe2x80x94(CH2)2xe2x80x94;
or R13 and R14 together form a C3-C7-alkylene chain which is closed to a ring and to which [lacuna] phenyl ring is fused, such as 2,3-dihydroindole, indole, 1,3-dihydroisoindole, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, it being possible for the phenyl ring in each case to be substituted one to three times by halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, hydroxyl, carboxyl.
The groups R13 and R14 taken together must contain at least 5 carbon atoms.
R7 and R8 (which may be identical or different):
hydrogen, C1-C4-alkyl.
R15 C1-C4-alkyl, C1-C4-alkoxy, each of which may carry one of the following radicals: hydroxyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, carboxamide [sic] or CON(C1-C4-alkyl)2.
R18 hydrogen;
C1-C4-alkyl, where each of these radicals can be substituted one to three times by: halogen, C1-C4-alkoxy, C1-C4-alkylthio, C3-C8-cycloalkyl, phenoxy or phenyl, where the abovementioned aryl radicals for their part can be substituted one to three times by: halogen, C1-C4-alkyl or C1-C4-alkoxy;
C3-C8-cycloalkyl;
phenyl which can be substituted one to three times by: halogen, hydroxyl, R15, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted one to three times by: halogen, C1-C4-alkyl, trifluoromethyl, C1-C4-alkoxy;
R19 C1-C4-alkylcarbonyl, where each of these radicals can be substituted one to three times by: halogen, C1-C4-alkoxy, C3-C8-cycloalkyl, phenyl which can be substituted for its part one to three times by: halogen, C1-C4-alkyl or C1-C4-alkoxy;
C3-C8-cycloalkylcarbonyl;
phenylcarbonyl or naphthylcarbonyl, each of which can be substituted by one or more of the following radicals: halogen, R15, C1-C4-alkyl, C1-C4-alkoxy, phenoxy, dioxomethylene [sic], dioxoethylene [sic] or phenyl which can be substituted one to three times by: halogen, C1-C4-alkyl or C1-C4-alkoxy;
C1-C4-alkylsulfonyl, where each of these radicals can be substituted one to three times by: halogen, C1-C4-alkoxy, phenyl which for its part can be substituted one to three times by: halogen, C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkylthio;
C3-C8-cycloalkylsulfonyl;
phenylsulfonyl or naphthylsulfonyl, where each of these radicals can be substituted one to three times by: halogen, R15, C1-C4-alkyl, C1-C4-alkoxy, dioxomethylene [sic], dioxoethylene [sic] or phenyl;
R20 hydrogen, C1-C4-alkyl.
R21 hydrogen, C1-C4-alkyl.
W sulfur or oxygen;
The compounds of the present invention provide a novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, arrhythmia, acute/chronic kidney failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and bypass operations, benign prostate hyperplasia, ischemic and intoxication-induced kidney failure or hypertension, metastasis and growth of mesenchymal tumors, contrast agent-induced kidney failure, pancreatitis, gastrointestinal ulcers.
The invention furthermore provides combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin-II antagonists and angiotensin converting enzyme (ACE) inhibitors. Preference is given to combinations of endothelin receptor antagonists of the formula I and ACE inhibitors.
The invention furthermore provides combinations of endothelin receptor antagonists of the formula I and beta blockers.
The invention furthermore provides combinations of endothelin receptor antagonists of the formula I and diuretics.
The invention furthermore provides combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor). Such substances are, for example, antibodies directed against VEGF, or specific binding proteins, or else low-molecular-weight substances which are able to specifically inhibit VEGF release or receptor binding.
The abovementioned combinations can be administered simultaneously or sequentially. They can be employed both in a single pharmaceutical formulation or else in separate formulations. The application form can also vary, for example, the endothelin receptor antagonists can be administered orally and the VEGF inhibitors parenterally.
These combination products are particularly suitable for the treatment and prevention of hypertension and its sequelae, and for the treatment of cardiac insufficiency.
The good action of the compounds can be shown in the following experiments: [sic]
The invention furthermore provides a structural fragment of the formula 
in which the radicals R1, R4, R5, R6, R7, R8 and W are as defined above.
Such structural fragments are suitable as structural components of endothelin receptor antagonists.
The invention furthermore provides endothelin receptor antagonists comprising a structural fragment of the formula 
in which the radicals R1, R2, R3, R4, R5, R7, R8, W, X, Y and Z are as defined above, covalently linked to a group which has a molecular weight of at least 30, preferably 40.
The invention furthermore provides
endothelin receptor antagonists comprising a structural fragment of the formula 
xe2x80x83in which the radicals R1, R2, R3, R4, R5, R7, R8, R20, R21, W, X, Y and Z are as defined in claim 1, covalently linked via a nitrogen atom to a group which has a molecular weight of at least 58.
The invention furthermore provides compounds of the formula Ia 
in which the radicals R1, R2, R3, R4, R5, R7, R8, R20, R21, W, X, Y and Z are as defined in claim 1.
Receptor Binding Studies
Cloned human ETA or ETB receptor-expressing CHO cells were employed for binding studies.
Membrane Preparation
The ETA or ETB receptor-expressing CHO cells were grown in DmeM NUT MIX F12-medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM glutamine (Gibco No. 25030-024), 100 U/ml penicillin and 100 xcexcg/ml streptomycin (Gibco [sic], Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS at 37xc2x0 C. for 5 minutes. This was followed by neutralization with medium, and the cells were collected by centrifugation at 300xc3x97g.
For the membrane preparation, the cells were adjusted to a concentration of 108 cells/ml of buffer (50 mM tris.HCL [sic] buffer, pH 7.4) and then disintegrated by ultrasound Branson Sonifier 250, 40-70 seconds/constant/output [sic] 20).
Binding Assays
For the ETA and ETB receptor binding assay, the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4 with 5 mM MnCl2, 40 mg/ml Bacitracin and 0.2% BSA) in a concentration of 50 xcexcg of protein per assay mixture and incubated with 25 pM [125I]-ET1 [sic] (ETA receptor assay) or 25 pM [125I]-ET3 [sic] (ETB receptor assay) at 25xc2x0 C. in the presence and absence of of test substance. The nonspecific binding was determined with 10xe2x88x927 M ET1. After 30 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell harvester (Skatron, Lier, Norway) was carried out to separate free and bound radioligand, and the filters was washed with ice-cold tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.
In vivo Testing of the ET Antagonists
Male ST rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and the jugular vein were cathetized [sic].
In control animals, intravenous administration of 1 xcexcg/kg ET1 results in a distinct rise in blood pressure which persists for a lengthy period.
The test animals received i.v. injections of the test compounds (1 ml/kg) 30 min before the ET1 administration. To determine the ET antagonistic properties, the changes in the blood pressure of the test animals were compared with those of the control animals.
Oral Testing of the Mixed ETA and ETB Antagonists
Male normotensive rats (Sprague Dawley, Janvier) weighing 250-350 g are pretreated orally with the test substances. 80 minutes later, the animals are anesthetized with urethane and the carotid artery (for measuring the blood pressure) and the jugular vein (administration of big endothelin/endothelin 1) are catheterized.
After a stabilization period, big endothelin (20 xcexcg/kg, administration volume 0.5 ml/kg) or ET1 (0.3 xcexcg/kg, administration volume 0.5 ml/kg) is administered intravenously. The blood pressure and heart rate are recorded continuously for 30 minutes. The distinct and long-lasting changes in blood pressure are calculated as area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the substance-treated animals is compared with the AUC of the control animals.
The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.
The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active ingredient is about 0.5-50 mg/kg of bodyweight on oral administration and about 0.1-10 mg/kg of bodyweight on parenteral administration.
The novel compounds can be used in conventional solid or liquid pharmaceutical forms, e.g. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active ingredients can for this purpose be processed with conventional pharmaceutical auxiliaries such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain from 0.1 to 90% by weight of active ingredient.